Injuries to peripheral nerves can be caused by trauma, surgery, cancer and by congenital anomalies. Injuries to peripheral nerves can be also caused by radiation therapy, chemotherapy, metabolic/endocrine complications, inflammatory and autoimmune diseases, vitamin deficiencies, infectious diseases, toxic causes, accidental exposure to organic metals and heavy metals, drugs, amputations and disease or condition relating to a loss of motor or sensory nerve function. Nerve injury or lesion may include nerve transection, crush, compression, stretch, laceration (sharps or bone fragments), ischemia and blast. In addition, nerve injury or lesion may result from damage or disruption of the neuronal axons. Injuries to peripheral nerves can be also caused by radiation therapy, chemotherapy, metabolic/endocrine complications, inflammatory and autoimmune diseases, vitamin deficiencies, infectious diseases, toxic causes, accidental exposure to organic metals and heavy metals, drugs, amputations and disease or condition relating to a loss of motor or sensory nerve function. Nerve injury or lesion may include nerve transection, crush, compression, stretch, laceration (sharps or bone fragments), ischemia and blast. In addition, nerve injury or lesion may result from damage or disruption of the neuronal axons.
Peripheral nerve injury is a major source of morbidity and an area with significant medical need. Indeed, only 50% of patients achieve good to normal restoration of function following surgical repair, regardless of the strategy. Moreover, failure of nerve regeneration may necessitate amputation of an otherwise salvaged limb. This stems from the inadequacy of current PNI repair strategies, where even the “gold-standard” treatment—the nerve autograft—is largely ineffective for major nerve trauma, defined as loss of a large segment of nerve (i.e., >5 cm) or injury occurring closer to the spinal cord (e.g., shoulder, thigh) resulting in extremely long distances for axon regeneration to distal targets (e.g., hand, foot). Despite significant efforts, PNI repair has not progressed past nerve guidance tubes (NGTs) for the bridging of small gaps or come close to matching the performance of autografts. As a result, the field is in desperate need of a transformative technology for repair of peripheral nerve injury.
The key failing of all current strategies to functionally repair major nerve trauma is the inability to coax a sufficient number of axons to grow a substantial distance to reinnervate distal targets (e.g., hand) and restore function. To overcome this failing, repair strategies must address two major challenges: (1) encourage rapid regeneration of proximal axons and (2) maintain the pro-regenerative capacity of the distal nerve segment for regenerating axons.
Degeneration of the axon segments distal to a nerve injury site is an inevitable consequence of transection of or injury to the nerve; however, the supporting Schwann cells in the distal nerve segment survive and switch to a pro-regenerative phenotype to support axon growth. This pro-regenerative phenotype includes a change in cellular alignment to form parallel columns, providing tracts that serve as guides for regenerating axons. Unfortunately, the natural pro-regenerative environment degrades after several months without the presence of axons, thus depriving regenerating axons of their “road map” to an end target. This occurs when the time it takes to regenerate axons to infiltrate the distal segment is greater than the time the Schwann cells can maintain their pro-regenerative phenotype. Often, following long or proximal PNI, the pro-regenerative environment fails and there is incomplete functional recovery. For example, a patient with a PNI of the upper arm may regain elbow, but not hand function, due to the distance between the nerve injury and the end targets in the hand, which are often not reached by proximal axons before the distal environment is no longer pro-regenerative. In another example, a PNI is not treatable due to the large size of the nerve lesion or injury, irrespective of the lesion or injury location.
Various techniques for prolonging the pro-regenerative capacity of the distal nerve segment following nerve injury have been explored. These include providing neurotrophic factors (e.g., GDNF, BDNF, and TGF-beta) to the distal nerve segment; administering electrical stimulation to the nerve sheath in an attempt to stimulate acceleration of axon regeneration; and transferring a foreign sensory nerve or an adjacent healthy nerve to the denervated nerve sheath (known as “babysitting” techniques). However, such techniques are often limited by a lack of efficacy, particularly with regard to long-term efficacy. In addition, some of these techniques have the clear disadvantage of transecting a healthy nearby nerve for the purpose of transferring it to the adjacent denervated nerve stump.
Thus, there is a need in the art for more effective means of maintaining the pro-regenerative capacity of denervated distal nerve segments so that the effectiveness of current or future means of PNI repair can be increased. There is a particular need in the art for maintaining pro-regenerative capacity and alignment of Schwann cells in the denervated distal nerve segment long-term.